Is FREM2 p.Pro146Arg (c.437C>G) pathogenic?

FREM2 p.Pro146Arg (c.437C>G) is classified Conflicting classifications of pathogenicity in FREM2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.663); Rare (popmax 0.145%, sas); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Pro146Arg (c.437C>G)?

FREM2 p.Pro146Arg (c.437C>G) is associated with Inborn genetic diseases, isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Pro146Arg (c.437C>G) in the general population?

FREM2 p.Pro146Arg (c.437C>G) is rare (popmax 0.145%, sas) (gnomAD).

What do computational predictors say about FREM2 p.Pro146Arg (c.437C>G)?

AlphaMissense predicts likely pathogenic (score 0.663) — an in-silico prediction, not a clinical call.

FREM2 p.Pro146Arg

c.437C>G · rs564740435 · VCV2413596

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.663 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.145%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.663	likely pathogenic
REVEL	0.415	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.145% South Asian · 114/78,822 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.0152% 234/1,536,336 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.172%	580
South Asiangrpmax	0.145%	691
Middle Eastern	0.0524%	1,909
Remaining individualsnot grpmax-eligible	0.0136%	7,377
Admixed American	0.00576%	17,360
European (non-Finnish)	0.00536%	18,652
East Asian	0.00229%	43,592
African / African-American	0.00136%	73,392

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FREM2
Protein: p.Pro146Arg
Coding: c.437C>G
MANE Select: NM_207361
dbSNP: rs564740435
Type: single nucleotide variant
Location: chr13:38687781 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated cryptophthalmia Fraser syndrome 2

Similar variants

FREM2 p.Pro146Leu Uncertain significance ★ same residue
FREM2 p.Pro146= Likely benign ★ same residue
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg638Ter Likely pathogenic ★★ same condition
FREM2 p.Arg736Ter Pathogenic ★★ same condition
FREM2 p.Arg809Ter Pathogenic ★★ same condition
FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Gln717Ter Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/frem2-p-pro146arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown